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Synthesis of many different types of organic small molecules using one automated process - PubMed

  • ️Thu Jan 01 2015

Synthesis of many different types of organic small molecules using one automated process

Junqi Li et al. Science. 2015.

Abstract

Small-molecule synthesis usually relies on procedures that are highly customized for each target. A broadly applicable automated process could greatly increase the accessibility of this class of compounds to enable investigations of their practical potential. Here we report the synthesis of 14 distinct classes of small molecules using the same fully automated process. This was achieved by strategically expanding the scope of a building block-based synthesis platform to include even C(sp3)-rich polycyclic natural product frameworks and discovering a catch-and-release chromatographic purification protocol applicable to all of the corresponding intermediates. With thousands of compatible building blocks already commercially available, many small molecules are now accessible with this platform. More broadly, these findings illuminate an actionable roadmap to a more general and automated approach for small-molecule synthesis.

Copyright © 2015, American Association for the Advancement of Science.

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Figures

Fig. 1
Fig. 1. Common building block-based approach for making many different types of small molecules

(A) A collection of compounds representing the structural and functional diversity of small molecules. (B) Analogous building block-based strategies for the synthesis of peptides and small molecules. (C) Synthesis of the Csp3-rich pentacyclic secodaphnane core (±)-14 via iterative Csp3 couplings to yield a linear precursor followed by biosynthesis-inspired cascade polycyclization. An X-ray structure of the N-bromoacyl derivative of 14 was obtained to unambiguously confirm the structure of 14. TIPS = triisopropylsilyl.

Fig. 2
Fig. 2. General purification process to enable automation

(A) MIDA boronates uniformly show binary elution properties on silica gel thin-layer chromatography. (B) Photograph of the small molecule synthesizer which comprises three modules that execute the deprotection Ⓓ, coupling Ⓒ, and purification Ⓟ steps. (C) Automated synthesis of natural products, materials, pharmaceuticals, and biological probes via iterative coupling of building blocks indicated by different colors (24).

Fig. 3
Fig. 3. Automated synthesis of ratanhine derivatives

Conditions: deprotection – NaOH, THF:H2O; coupling – cycle 1: Pd(OAc)2, SPhos, K2CO3, THF, 55 °C, 16h. cycle 2: Pd(OAc)2, XPhos, K3PO4, THF, 55 °C, 14 h. cycle 3: Pd(OAc)2, SPhos, K3PO4, THF, 55 °C, 24 h; purification – SiO2, MeOH:Et2O; THF. All protecting groups other than MIDA (R = TIPS, TBDPSE, TMSE, or Bz) were successfully removed in a separate step (24).

Fig. 4
Fig. 4. Synthesis of Csp3-rich macro- and polycyclic natural products and natural product-like cores

Modular linear precursors assembled via automated Csp2 and Csp3 couplings are diastereo- and/or enantioselectively cyclized.

Comment in

  • The synthesis machine.

    Service RF. Service RF. Science. 2015 Mar 13;347(6227):1190-3. doi: 10.1126/science.347.6227.1190. Science. 2015. PMID: 25766215 No abstract available.

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References

    1. Merrifield RB. Science. 1965;150:178–185. - PubMed
    1. Caruthers MH. Science. 1985;230:281–285. - PubMed
    1. Plante OJ, Palmacci ER, Seeberger PH. Science. 2001;291:1523–1527. - PubMed
    1. Ley SV, Fitzpatrick DE, Ingham RJ, Myers RM. Angew Chem Int Ed. 2015;54 doi: 10.1002/anie.201410744. - DOI - PubMed
    1. Fuse S, Machida K, Takahashi T. In: New Strategies in Chemical Synthesis and Catalysis. Pignataro B, editor. Chapter 2 Wiley-VCH; Weinheim, Germany: 2012.

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